By Swati Patel and Michael Lanewala, Clarkston Consulting
Messenger RNA technology is a promising platform that offers faster and simpler methods for treating and preventing diseases. It continues to grow its presence as companies look to apply the technology beyond the COVID mRNA vaccine. However, planning and procuring custom materials needed to manufacture mRNA remains one of the top concerns for companies.1
Here are approaches to alleviate some of the challenges associated with using custom raw materials:
While these strategies may be applied to other raw materials, the recommendations below are intended for mRNA production. Let’s take a closer look at each of these approaches.
Moving to a dual or multi-sourcing strategy for custom raw materials is one method that companies can implement to reduce supply risk associated with single sourcing. Having more than one supplier for a given material can reduce variability in the production plan that may be caused by capacity constraints and/or quality issues. It also provides a backup option when unexpected issues arise that may require additional and/or new material.
While finding an alternate supplier seems like an obvious decision, companies are not able to easily adopt this strategy because it not only requires time, resources, and commitment but also imposes a new set of concerns.
Suppliers must be qualified before their materials can be used for GxP purposes. The qualification process requires resources to organize, conduct, and review vendor audits. In addition, once a supplier is onboarded, companies need resources to manage relationships with the new supplier, establish proper communication and visibility to their production plan, and ensure they can meet supply needs. Hence, corporate sponsorship and resource availability is a must to adopt a multi-sourcing strategy.
Product quality between vendors may differ, leading to differences in the final product depending on the raw material used. A thorough qualification process can help to reduce this concern, but another potential workaround is to split programs by supplier. For example, if Program A only uses material from Supplier 1 and Program B only uses material from Supplier 2, the overall demand for the business can be met and material differences between suppliers will be mitigated. This can also be helpful if programs are split geographically, as suppliers near each manufacturing site can be used for their site-specific programs.
Splitting demand between suppliers will likely lead to reduced purchasing volume at each supplier, which can have pricing impacts as volume discounts may not be available. In addition, if one supplier is only utilized occasionally, it may be more prone to manufacturing defects because it is not producing the material as much, or the cost of keeping the entity qualified outweighs the benefit of having an alternate source.
A strong sales and operations planning (S&OP) process (or demand and operations planning if there are no commercial sales) is a must-have to ensure Supply Chain has clear visibility into the business requirements. Leadership must buy into the necessity of the process and enforce with all groups the criticality of timely communication of changes to the manufacturing plan. At a minimum, the quantity needed for the current year must be known, but as the lead time on many of the materials can be six to nine months, a two- to three-year visibility window will help Supply Chain plan more accurately.
Business units need to understand the impact of their changes to the custom material production plan. Due to the long lead times, Supply Chain needs to lock batches into suppliers’ schedules as soon as possible. There will likely be some flex in the schedule, but as purchasing will be driven by the total demand in a given period, the sooner batches are locked into the schedule, the better the pricing and chance for on-time delivery. Additionally, as larger-scale batches become necessary, suppliers may need to scale up their operations to meet raw material requirements. Without appropriate visibility, suppliers will not be able to meet demand and critical milestones may be missed.
The S&OP process can also help identify where there are inefficiencies in batch sizes or number of batches being produced and course correct accordingly. If a group is manufacturing 10 g of material but only 5 g of material will be consumed downstream, examining the rationale for the batch size and potentially resizing to account for downstream processes can reduce total demand and purchasing requirements. Alternatively, additional material produced can be used for training or test batches when transferring new processes or establishing a new program. It might also be possible to combine batches (training and water run batches, for example) to reduce overall raw material demand. Visibility and communication are the keys to better planning.
Lastly, the S&OP process is particularly important for prioritizing supply across multiple programs. Business units should discuss each program and batch criticality collectively. If supply requirements cannot be met, which batches should be selected to continue? There are many possible factors to consider, such as regulatory demands, clinical trial demands, and corporate strategy. Ultimately, the group must decide which batches are more critical to complete than others.
Adjusting the packaging size can be used to help address some of the risks associated with mRNA custom raw materials.
With custom raw materials, it is unlikely that freeze/thaw studies have been performed. Without data confirming the efficacy of thawing a material, using some of it, and refreezing the remainder, the entire batch that is thawed must either be used, or unused portions must be discarded since there is no evidence. By using packaging sizes that reflect the amount of material required by the Bill of Materials (BOM) and adjusting the manufacturing batch size for the raw material accordingly, you can remove the freeze/thaw risk. For example, if the most common batch size is 10 mg and the BOM calls for 1 g of raw material per mg of final product produced, you could work with the supplier to get 10 g or 5 g packaging sizes to ensure the entire container is used in a batch.
Packaging size can also help account for the difficulties that arise from the physical properties of some of the raw materials. Custom lipids, for example, can be highly viscous and difficult to measure accurately. If the batch requires 20 mL of material and the package contains 30 mL, measuring the correct amount of raw material can be extremely difficult, with additional material loss during the transfer. Using a packaging size that reflects the amount of material required for the batch can remove the difficulty of measuring the material, as the entire container can be used.
One of the major risks for custom raw materials is expiry. Purchasing quantities to meet production demand that is not realized can lead to large amounts of expensive materials not being consumed, especially when expiries are being constantly evaluated. Ultimately, your tolerance of this risk will define your purchasing and inventory strategy for custom raw materials. If your risk tolerance is low, then overordering and/or maintaining safety stock to ensure custom raw material availability will help reduce risk but carry high costs and inventory levels. If safety stock inventory is not used timely, it can result in higher levels of expired materials. Hence, determining the right level of safety stock will be dependent on your risk tolerance.
Conversely, if your risk tolerance is high, then reducing inventory as much as possible and rescheduling batches can help keep costs down. One way to reduce expired material inventory is to find alternative uses for the material. If you’re using a platform strategy where each product shares the same custom raw material, then it’s possible to shift unused portions to another program and reduce future procurement spending. You can also shift material from GxP to non-GxP uses. R&D is more likely to consume the material as they are able to use expired materials (after retesting to ensure functionality). Another option is to conduct stability studies to extend the shelf-life expiration. Companies need to invest in stability studies that can help extend expiration, which can either be performed internally or be outsourced. A product platform strategy can also help with extending expiry dates for custom materials, as earlier lots on stability can be used to extend the expiry date of lots purchased or manufactured later.
Companies embarking on mRNA production will need to procure custom raw materials, which pose new challenges, such as long lead times, limited suppliers, small batch quantities, and ever-changing and developing expiration periods. While there is no silver bullet, implementing one or all of the strategies discussed above can help companies better plan and fulfill their manufacturing demands.
About The Authors:
Swati Patel is a director of life sciences at Clarkston Consulting, with more than 25 years of experience working in the life sciences industries. She has worked with many of the top pharmaceutical and biotech companies to implement global ERP solutions, provide program/project management for strategic and large-scale initiatives, and support clinical biotech companies’ transition into commercial organizations.
Michael Lanewala is a manager at Clarkston Consulting with 20 years of experience working within the life sciences. He has worked primarily with clients in the pharmaceutical and biotech industries, specializing in project management and the development of technical solutions, and also has extensive experience with the implementation of quality systems, especially laboratory information management systems (LIMS).
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